PharmTech.com
2015
SOLID DOSAGE AND
EXCIPIENTS
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TABLETING
4 Advances in Tableting
Cynthia A. ChallenerTASTE MASKING
12
Assessing and Improving
the Palatability of Pharmaceuticals
Muhammad Ashraf, Frank Holcombe, Jr., Vilayat Sayeed, and Siva VaithiyalingamORAL DOSAGE FORMULATION
24
Using Polymers for More Efficient
Hot-Melt Extrusion and Spray Drying
Kevin P. O’Donnell, William W. Porter III, and True L. RogersANALYTICAL TECHNIQUES
34
Analytical Techniques
for Oral Solid Dosage Formulation
Paul Kippax and Deborah Huck-JonesPROCESS ANALYTICAL TECHNOLOGY
40 Simplify Formulation With PAT
Emil W. CiurczakLIPID FORMULATIONS
44
Boosting Solubility in
Lipid-Based Formulations
Agnes ShanleyNEW TECHNOLOGY
48
Innovations in Solid Dosage Equipment
Ashley RobertsIssue Editor: Agnes Shanley
On the Cover: Snap Decision/Mandy Disher Photography/Jonathan Kitchen/ Lauren Burke/KidStock/Adam Gault/Getty Images.
EDITORIAL
Editorial Director Rita Peters [email protected] Senior Editor Agnes Shanley [email protected] Managing Editor Susan Haigney [email protected]
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Contributing Editors Jill Wechsler [email protected]; Jim Miller info@ pharmsource.com; Hallie Forcinio [email protected]; Susan J. Schniepp
[email protected]; Eric Langer [email protected]; and Cynthia A. Challener, PhD [email protected]
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F
or many reasons—from ease of administration to dosing ac-curacy to manufacturing efficiency—pharmaceutical manu-facturers prefer to formulate their APIs as solid dosage drugs, and particularly tablets. There is significant room, however, for improvement of tableting processes. Advances in tableting technology, including continuous production equipment and the process analyti-cal technology (PAT) and software required for effective continuous commercial-scale production, are helping to increase reproducibility, accuracy, and consistency. These aspects of production impact the quality, safety, and efficacy of formulated tablets. Modeling systems designed for use in industry have also been developed that are improv-ing the ability of formulators to better correlate raw material properties and processing conditions with the properties of the finished tablet. Key advances for the future will lie in the ability of different equipment and software suppliers to work together to develop tableting systems that can be truly integrated for complete continuous processing.Tablet press lubrication
Lubricants (commonly magnesium stearate) affect the tableting pro-cess and the finished tablet. They not only reduce the compression force during tableting, but also prevent product buildup on tablet press tools and give the tablet a smooth surface. Too much lubricant can, however, reduce the hardness of the tablet to an undesired level, according to Sharon Nowak, business development manager with Coperion K-Tron Food & Pharmaceutical Industries. Traditionally, lubricants have been mixed with the solids used to form tablets, but this approach often leads to non-uniform distribution of the lubri-cant. To compensate, excess lubricant is used, which can negatively affect tablet properties.
Advances in Tableting
Cynthia A. ChallenerInnovative equipment, analytical techniques, software, and modeling systems are improving the tableting process.
Cynthia A. Challener, PhD,
is a contributing editor to Pharmaceutical Technology.
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Recently, equipment has been developed that al-lows for spraying of the lubricant onto the tablet press tooling, allowing for significant reduction in the quantity of lubricant required. Original sys-tems sprayed powdered lubricants on to the tab-let press tooling to prevent sticking of the powder to the tool and die of the tablet press, according to Nowak. Importantly, these applications were done primarily volumetrically, with no measure-ment of the actual weight of the lubricant delivered. Magnesium stearate does not flow well, which can cause high variations in the feed rate with volu-metric feeders because of inconsistent filling of the twin screws. As a result, there has been an in-creased demand for automated tablet press lubrica-tion systems with highly accurate gravimetric feed designs, according to Nowak.
“High accuracy twin-screw gravimetric feeders quantitatively deliver a specific amount of lubri-cant to the tablet. They also allow accurate deter-mination of the amount of lubricant delivered to each tablet, even though the quantity of lubricant that ends up in the tablet granulation formulation is significantly decreased,” she observes. As a re-sult, not only are the material handling properties of the granulation process improved, the overall dissolution rates of tablets can be increased. The lower quantities of lubricants required for tablet-ing have also led to a need for lower and lower feed rate deliveries, according to Nowak. “For this reason, automated lubricant feeding systems today require highly accurate, specialized low-rate feed-ing,” she says.
Coperion K-Tron’s solution uses patented load cell technology that continuously measures the weight of the lubricant and maintains a constant mass flow (weight per unit of time) by adjusting
the speed of the twin-screw feeder. As a result, ac-cording to Nowak, the unit can be validated for a steady and uniform feed of lubricant to the tablet press. In addition, because the lubricant is deliv-ered to the tools in a fraction of a second, the short-term accuracy is high. “With a nearly constant feed rate, it is possible to achieve uniform coating of the tablet tools and eliminate sticking problems, all with reduced stearate consumption and lower overall operating costs,” Nowak states.
Multi-tipped tooling and advanced coatings
The key drivers in tablet manufacturing are the need to increase yield and capacity while reduc-ing manufacturreduc-ing costs and minimizreduc-ing the space used and the time spent setting up each press, and increasing productivity has always been a chal-lenge in modern tablet production, according to Steve Deakin, owner director of I Holland. That is why he believes the widespread use of multi-tipped tooling and the continued development of punch-and-die treatments and coatings have been great advances in the pharmaceutical industry.“Our ongoing development of multi-tip tooling is specifically driven by the desire to assist our cus-tomers in increasing productivity and capacity,” he says. Multi-tip punches allow the number of tablets per turret rotation to be multiplied by the number of tips on the punch. They also require less floor space, because more tablets can be produced with fewer tablet presses, leading to a reduction in overall plant running costs. “The development of a technology like multi-tip tooling is beneficial to many end users,” says Deakin.
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corrosion resistance, and improving anti-stick properties. “Treatments and coatings with these properties can help preserve the life of our punches and increase productivity for our customers,” Dea-kin comments. “The overall result is reduced press downtime and increased productivity, which is what every company wants,” he adds.
Continuous manufacturing, QbD, and PAT
The development of effective equipment for con-tinuous tablet production—from feeders to tablet-ing machines to coaters—has had a major impact on the growing adoption of continuous processing. Pharmaceutical companies are also beginning to understand the significant benefits that continu-ous tableting can bring, from increased produc-tivity and quality to increased manufacturing and marketing flexibility. “The focus on continuous manufacturing of solid oral dosage forms by large pharma companies like Pfizer, Merck, Eli Lilly, and Vertex is a notable sign that batch process methods are waning and the move toward continuous man-ufacturing is accelerating when the application is appropriate,” according to Charles N. Kettler, di-rector of Natoli Scientific, a business unit of Na-toli Engineering Company. He also notes that the use of quality-by-design (QbD) concepts and PAT dovetail nicely with the continuous manufacturing architectures that are being developed. PAT has, in fact, advanced to a point where manufacturers can have confidence in the determination of product quality throughout the process.
Need for systems integration
and data management
The marriage of the unit operations needed to build a continuous manufacturing process is,
how-ever, requiring the vendors of these singular units to be open to the needs of control engineers so that the movement of the product through the process can occur seamlessly with the support of the data required to meet the needs of the control strategy, according to Kettler.
Nowak notes, for example, that the increase in continuous direct compression tablet manufacture is requiring high integration between the ingre-dient feeders, PAT instrumentation, and the ad-ditional system components from the blending operation and the tablet press. “For this reason, advanced control systems and common protocols, PAT technology, and the advanced ingredient feeder control modules supplied by Coperion K-Tron that provide totalizer ingredient line control based on the API feeder performance for multiple feeders to a continuous line will be important and require even further innovations,” she says.
Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2015 9
will provide the energy needed to overcome those barriers, and that opportunities will present them-selves in 2015.
The move to continuous processing also pres-ents data management challenges. The coupling of complex processes such as high shear wet gran-ulation with fluid bed drying and blending and ultimately a tablet press will result in the genera-tion of a significant amount of data. Multivariate measurement technologies (PAT systems) also gen-erate large quantities of data. “The challenge will be to evolve a batch record that meets regulatory requirements, thus protecting the patient, but is not so onerous in size that it cannot be utilized for ongoing process improvement,” Kettler observes. He does note that statisticians, chemometricians, and quality assurance experts are already work-ing to address this challenge, but the industry will need to work with regulators to ultimately develop workable solutions.
Outside of continuous manufacturing, advances in information technology have already been re-sponsible for increased tablet press capability and controls, according to Deakin. “Modern systems can provide detailed information relating to the operation and performance of the tablet presses and help link downstream processes to ensure quality control. The use of these technologies has both improved tablet quality and enhanced pro-duction performance and capacity,” he asserts.
Modeling for improved performance
Despite the significant advances in tableting tech-nology, including online monitoring with PAT systems and the move to continuous production operations, the tableting process in many ways re-mains inefficient and variable. This inefficiency is
due to a lack of process understanding with respect to the impact that raw material properties and pro-cess conditions have on final tablet properties. In-creasingly, formulators and process engineers are turning to predictive process modeling as a means for increasing process understanding and reducing variability.
I Holland, in collaboration with the University of Nottingham’s Laboratory of Biophysics and Sur-face Analysis, United Kingdom, recently developed a predictive model (TSAR≈Predict) that enables the identification of the appropriate anti-stick punch coating solution from I Holland for formu-lation-sticking issues without the need to carry out expensive and time-consuming, full-scale, trial-and-error experiments with several anti-stick coat-ings. The model considers the properties of the API and any excipients, possible Van der Waals forces, capillary action, deformation mechanics, the com-pression environment, and the chemistries of dif-ferent coatings.
Discrete element and finite element method (DEM/FEM) models are more established for the simulation of the behavior of bulk solids during processing. DEM has been used, for example, to predict powder packing and flow behaviors. DEM Solutions offers its EDEM software platform for the optimization of bulk solids handling and pro-cessing equipment, according to the company. Properties such as the particle size and shape distribution, mechanical strength and stiffness, surface roughness, stickiness, chemical reactivity, and surface charge are considered in the EDEM models.
models that reduce the complexity, and thus the time and expense required to complete the calcula-tions (1). This reduction can be achieved with mul-tivariate analysis techniques or lower dimensional models that are developed by fitting experimen-tal or simulated data using a range of techniques, including kriging, response surface methodology, artificial neural networks, or high dimensional model representation (1).
The company Process Systems Enterprise offers its gPROMS modeling platform, which consists of the ModelBuilder model development envi-ronment and gSOLIDS and gCRYSTAL specialty applications for solids processing. This modeling software also offers a process flowsheeting envi-ronment, which allows the development of inte-grated flowsheet models for process simulation
and optimization and the identification of appro-priate control strategies, often with data from a reduced number of experiments (1).
Despite advances in the development of predic-tive models for pharmaceutical tableting processes, they still fall short of the desired level of perfor-mance. Models that better link particle properties to a wider set of bulk powder properties during processing and more accurately predict the impact of changes in raw materials and the manufactur-ing process on tablet properties are needed, as are new approaches that enable more complex model-ing without increasmodel-ing the computation time and expense (1).
Reference
1. A.J. Rogers, A. Hashemi, and M.G. Ierapetritou, Processes 1(2), 67-127 (2013). PT
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FORMUL
A TION
COMMERCIAL ANAL
YTIC
AL CLINIC AL
T
he Merriam-Webster Dictionary defines palatable as “agree-able to the palate or taste” or “agree“agree-able or accept“agree-able to the mind” (1). Taste, therefore, depends on both physiological and psychological phenomena, and is known to vary in hu-mans based on such factors as age, ethnicity, and geographic location. The human tongue has approximately 10,000 taste buds (2), or recep-tors, capable of detecting taste. Pharmaceutical product palatability is generally characterized based on bitterness, saltiness, sourness, and sweetness (3).These receptors excite specific neural pathways and, as a result, the information is processed along with other immediate olfactory, visual, and somatosensory inputs, as well as those from memory (4). Several factors influence taste, including experience. Reluctance to take a bitter medication reflects human evolution, during when humans learned to reject harmful or poisonous materials, which tend to taste bitter (5).
Developing palatable drugs is key to breaking through this evolu-tionary barrier, and helps to improve patient compliance with treat-ment regitreat-ments. Currently, palatability is a factor in noncompliance, which can lead to treatment failure (6) and increased resistance to drugs, raising overall healthcare costs (7).
Taste is especially important in treatments designed for children. In one study on children infected with HIV, for example, one third of the patients failed to comply with the dosage regimen for a particular drug, due to their perceptions of the drug’s taste (8). In another in-vestigation, pediatric patient compliance with dosage regimen ranged from 11% to 93%.
Poor compliance or non-compliance typically places children at risk for such problems as continued recurrence of disease. In
addi-Assessing and Improving the
Palatability of Pharmaceuticals
Muhammad Ashraf, Frank Holcombe, Jr.,Vilayat Sayeed, and Siva Vaithiyalingam
Taste may be subjective, but it is crucial to patient compliance, particularly for pediatric treatments. This article reviews methods used to improve and assess pharmaceutical palatability.
Muhammad Ashraf is product
quality reviewer; Frank O.
Holcombe, Jr. is chemist; and
Vilayat Sayeed is supervisory
chemist all with FDA’s Office of Lifecycle Drug Products, OPQ, CDER. Siva Vaithiyalingam is director of regulatory affairs with
Teva Pharmaceuticals USA.
Please address all correspondence to [email protected]
Disclaimer: The views and opinions presented in this article are those of the authors and do not necessarily reflect the views or policies of FDA.
tion, it complicates the physician-patient relation-ship, and prevents accurate assessment of the qual-ity of care provided (9).
Ten years ago, a study published in the Neth-erlands recommended that regulatory authorities and the pharmaceutical industry ensure that chil-dren have access to more palatable medicines (10). To address this universal concern and to provide incentives to the pharmaceutical industry, the US Congress enacted the following legislation:
• The Best Pharmaceuticals for Children’s Act (BPCA 2002)
• The Pediatric Research Equity Act (PREA 2003)
• The FDA Amendment Act (FDAAA 2007). Today, advances in pharmaceutical technology make it easier to design and develop such child-friendly products as oral films, medical chewing gum, suspensions, and chewable tablets to name a few, wherein taste-masking agents can be incporated to conceal and counter the unpleasant or-ganoleptic attributes of drug substance.
Finding some common ground for taste-masking and pediatric friendly formulation, however, is not an easy task. Standard combinations of specific sweet-eners with relevant flavors may vary by country and target market. For instance, flavors such as “bubble-gum” and “grape” are preferred flavors in the United States, whereas “citrus” and “red berries” are popular in Europe, and licorice in Scandinavia (11).
The European Pediatric Formulation Initiative (EPFI) was founded in 2007 to address some of these issues and raise awareness of the importance of palatability in drug formulation. The initiative is focusing on such issues as taste assessment, ex-cipients, delivery devices, and extemporaneous preparations (12).
This article reviews the various technological platforms available for taste-masking, taste modifi-cation, and taste assessment, and touches on some of the risk management challenges associated with making palatable drugs products.
To mask or modify the taste of bitter compounds, pharmaceutical formulators must understand the chemistry of the API, identify solutions to re-duce or inhibit the bitter taste of the API without changing other flavor modalities (e.g., sweet, salt, or sour) and then choose the best taste technology platform to develop the drug product.
Some of the most commonly used taste-masking approaches include:
• Natural and artificial flavors and sweeteners
• Polymer coatings
• Multiple emulsion and liposomes
• Inclusion complexes
• Ion-exchange complexes
• Pro-drugs and salt formation.
The taste-masking technology should be care-fully aligned with the drug product dosage form, patient population, and duration of therapy.
Flavors, sweeteners, and other ingredients
Adding flavors and sweeteners is usually the first choice for improving the taste of a pharmaceutical formulation. Liquid flavors are used most often, because they diffuse readily into the substrate. They are available both as oily (e.g., essential oils)
Taste is especially
Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2015 15
or non-oily liquids. Their texture generally de-pends on the solvent within which they are pre-pared (13).
Flavor systems, however, can often feature func-tional groups, such as aldehydes, ketones, esters, or terpenes that can interact with actives and other ingredients in the formulation (14).
In addition, flavors are typically volatile and may degrade during the product’s shelf life. They can also be degraded by pH-catalyzed, oxidation-reduction, and hydrolytic reactions.
To ensure stability and prevent unacceptable changes in the flavor of a product, flavor systems must be compatible with other ingredients. In some cases, for example, flavor systems may be combined with antioxidants to reduce free radical autoxidation.
Besides traditional sweeteners and f lavors, other additives can be used to improve the taste of pharmaceutical formulations. These include amino acids and their salts (e.g., alanine, taurine, glutamic acid, and glycine), which are known to reduce the bitterness of drugs. Some patients, for example, found that the taste of ampicillin improved markedly when its granules had been prepared with glycine and mixed with additional quantity of glycine, sweeteners, flavors, and finally compressed into tablets (15).
Lipoproteins can also be effective in suppress-ing the bitter taste of basic and hydrophobic drugs. Incorporating it into a liposomal formulation with egg phyosphotydyl choline (16), for example, suc-cessfully masked the bitter taste of chloroquine phosphate in HEPES (N-2-Hydroxyethylpipera-zine -N’-2) -ethane sulfonic acid) buffer at pH 7.2 Increasing the viscosity of liquid formulations with thickening agents such as polyethylene glycol,
sodium carboxy methylcellulose, gums, or carbo-hydrates can also mask bitter taste by lowering the rate of diffusion of bitter substances from the sa-liva to the taste buds. Acetaminophen suspension, for example, has been formulated with xanthan gum (0.1-0.2%) and microcrystalline cellulose (0.6-1%) to reduce bitter taste, while the antidepressant mirtazapine has been formulated as an aqueous suspension using methionine (stabilizer) and maltitol (thickening agent). Maltitol, stable in the acidic pH range of 2 to 3, has the added benefit of inhibiting the drug’s undesirable local anesthetic effect (17–18).
Flavors and sweeteners have also been used to mask unpleasant taste in orally disintegrating tablets (ODTs) (19) and rapidly dissolving films (RDFs). For example, mannitol and licorice, and sugar-based excipients, using glucose, sucrose, su-cralose, and fructose and other ingredients have been used to improve the flavor of ODT formula-tions (20–22).
Sucralose, which is 600 times sweeter than sugar, has been used with mint and licorice flavors to mask the taste of diclofenac sodium maltodextrin RDFs (23). The films were prepared by casting and drying aqueous mixtures of maltodextrin, glycerin, sorbitan oleate, and diclofenac sodium. The taste-masking agents were added in very low concentra-tion (sucralose, mint, and licorice at 1%, 6%, and 3% w/w) and did not significantly affect the tensile properties and film disintegration time.
Polymeric coatings
Polymers that are insoluble in saliva are fre-quently used to mask the bitter taste of some drugs. The cationic copolymer, Eudragit E100 amino methacrylate copolymer, for example, can be used to coat the microspheres used in suspensions, and the granulations used in ODTs. The polymer’s pH profile helps ensure that active ingredient is released in the stomach and not in the mouth, because Eudragit E100 is soluble below a pH of 5 in the stomach, but insoluble in saliva, where the average pH is 6.4 (25). Granulations coated by the polymer, how-ever, can rupture during compression or tablet chewing, and patient tests show that they can contribute to a gritty feel in the mouth. Micro-spheres coated with the same material did not rupture.
Eudragit E100 can also be used in spray drying processes. In one process, the polymer was used to coat microspheres of donepezil hydrochloride, using spray-drying technology (26). In this study, a drug-to-polymer ratio of 1:2 was found to pre-vent drug release in simulated salivary fluid. The taste-masked microspheres were then formulated into an ODT.
In another example, taste-masked microspheres of famotidine were prepared by spray drying a sus-pension of finely ground famotidine (5 micron) in an aqueous dispersion of Eudragit EPO (15%, w/v). The microspheres were then mixed with other tableting ingredients suitable for ODT and com-pressed into tablets (27).
Techniques such as solvent diffusion, precipita-tion, and multiple emulsion have also been used to process polymer-coated pharmaceuticals. For instance:
• Eudragit E100 has been used to coat
micro-particles of Indinavir, a bitter-tasting HIV drug, by using a double emulsion solvent dif-fusion technique. The microparticles were then used to make a pediatric suspension (28).
• Eudragit EPO, an aminoalkyl methacrylate
copolymer was complexed with Ondansetron HCl, a bitter-tasting drug using precipitation. The best results were seen at a drug-to-poly-mer ratio of 8:2, and results were evaluated by dissolution in simulated salivary fluid of pH 6.2 and then in human volunteers. The taste-masked drug-polymer complex was then for-mulated into an ODT using spray-dried man-nitol, microcrystalline cellulose, and
Polyplasdone XL-10 (29).
• The natural polymer, chitosan, has also been
used to mask bitter taste in microspheres of Ondansetron HCl. Chitosan, a high molecu-lar weight, polycationic polyamine, linear polysaccharide derived from crustacean shells, readily dissolves in inorganic acids but is insoluble approximately above pH 6.5 (30). A 1:1 drug-to-polymer ratio successfully achieved taste-masking without any chemical interaction and loss of crystallinity (31). These polymers have also been used as binders for the manufacture of granulations of bitter tast-ing drugs. The taste-masked granulations can be further formulated into various types of tablet dos-age forms such as ODTs and chewable tablets. In tests, tablets of Zidovudine, a bitter-tasting antiret-roviral drug prepared by a wet granulation method using Surelease as binder, were found to taste better than tablets prepared by direct compression (32).
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using extrusion and compression (33). Eudragit E, which dissolves in acidic environments, has been used with Fattibase, a mixture of palm, palm ker-nel, and coconut oil triglycerides that melt at body temperature, to develop coatings for drug particles that mask bitter flavors. The coated particles were used to make liquid suspensions, and testing found that flavor had been masked completely (34).
Multiple emulsions
Taste-masking can be also be achieved by incor-porating drugs into the inner aqueous phase of water-oil-water (W/O/W) multiple emulsions, in which either the oil layer or the water layer masks the test. This approach has reportedly worked for formulations of chloroquin phosphate and chlor-promazine (35).
Inclusion complexes
Inclusion complexes with cyclodextrins have been used to improve the palatability of drug substances. Cyclodextrins are cyclic oligosaccharides, which have the ability to form a host/guest inclusion com-plex both in solution and in solid phase. Molecules or functional groups causing unpleasant taste can be encapsulated within the cyclodextrin cavity, so that they do not come in contact with the taste bud. Once the drug substance forms an inclusion complex with cyclodextrin, it exhibits properties different than those of the parent drug substance, such as improved dissolution and taste.
The taste-masking effect of various types of cy-clodextrin complexes may be correlated to their respective association constants. It is reported that β-cyclodextrin provides the highest taste-masking effect for cetirizine, while α and γ cyclodextrin provide the poorest results. The association
con-stants for α and γ cyclodextrin were found lower when compared to the association constant of β-cyclodextrin (36).
Similar results were reported in studies of the taste-masking effect of cyclodextrins on such an-tihistamines as hydroxyzine, cetirizine, and dl-chlorpheniramine. The taste-masking was found related to the respective association constant de-creasing in the following order: Hydroxy propyl β cyclodextrin, β cyclodextrin, α cyclodextrin, and γ cyclodextrins. Studies found that primaquine phosphate’s bitter taste was completely masked by formation of inclusion complex with β cyclodex-trin (37–39).
Ion-exchange resins
Ion-exchange resins have also been used to mask flavor in pharmaceuticals. These resins are high molecular weight, water-insoluble polyelectrolyte polymers that are not absorbed by the body and therefore are safe for oral use. These polymers have extensively charged cationic and anionic functional groups, which can form complexes with ionizable drugs via ion-exchange. The resulting drug-resinate possesses the properties of resin.
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of our materials are tested for quality by our in-house metallurgist and an independent lab.
Prodrugs and salt formation
It is postulated that bitter taste is perceived when a bitter-tasting drug binds directly to taste recep-tors. This binding, however, depends on molecular geometry. Changing this geometry by derivative formation will alter the affinity of the drug mol-ecule to the taste receptor. Several antibiotics such as Chloramphenicol palmitate or phosphate esters for pediatric suspension and alkyl esters of Clinda-mycin and ErythroClinda-mycin show how prodrugs can be used for bitter taste-masking.
Conversion of a drug to a salt has also been found to mask bitter drug taste by altering the chemical group that is responsible for the bitter taste. An ex-ample of this approach is chlorpheniramine male-ate, a taste-masked salt of chlorpheniramine base. Testing has shown that the alkyloxy alkyl
carbon-ates of clarithromycin have remarkably drecreased bitterness and improved bioavailability (43–46).
Measuring palatability: Art or science?
Taste assessment for pharmaceutical products is complicated, due to the qualitative measurement and the inherent differences and preferences among the subjects. It becomes even more dif-ficult when the taste assessment involves the pedi-atric population. For instance, in one such study, the end point-of-taste assessment was based on se-lecting a face from a list of five faces that portrayed happiness to sadness progressively (47).
Such an assessment rating scale, as concluded by the study authors, has the following limita-tions. First, the taste was assessed indirectly, and secondly, the subjects can be influenced by their own perception of the odor or taste of the product, and finally, there is no universal standard used in the study.
The use of analytical devices in the drug-develop-ment phase has improved the taste-assessdrug-develop-ment pro-cess, and this has led to a more robust, reproducible taste assessment method using objective electronic devices such as electronic tongues. These are es-sentially analytical instruments made of chemical sensors with specificity to different compounds in the solution. These sensors are non-specific, low selective chemical sensors with partial specificity for cross-sensitivity to a range of organic and inor-ganic substances in solution, and they are coupled with chemometric data processing tools (48).
A typical electronic tongue is based on potentio-metric or voltapotentio-metric sensors; however, in theory, any kind of sensor could be built into an electronic tongue. What is more important is that an appro-priate set of sensors responds to a range of com-pound taste attributes, and takes into account such interactions as suppression as well as synergetic effects, so that sensor responses represent human perception end points (49).
Several studies have utilized electronic tongues to assess the taste of the pharmaceutical product. In one case, an electronic tongue was used to select a taste-masking agent in the manufacture of diclofe-nac fast-dissolving film (27). The authors concluded that the electronic tongue allowed them to discern the effect of a taste-masking agent in the presence of other hydrosoluble constituents of the film.
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The electronic tongue is often used to screen the taste-masking effect of sweetening agents in phar-maceutical formulations. In one case, the electronic tongue was used to investigate the taste-masking effect of glucose, sucrose, sucralose, fructose, man-nitol, sodium saccharin, acesulfame potassium, monoammonium glycyrrhizinate, and other sweet-ening agents, to formulate liquid quinine hydrochlo-ride (51) as well as other drugs (52–54).
Risk considerations
The choice of flavors, sweeteners, and polymers used in the taste-masking platform should be care-fully aligned with the dosage form, patient popu-lation, duration of therapy, and the levels of these ingredients listed in the CDER approved products. This information is available in the Inactive In-gredients Database (IID) of CDER approved drugs. Amounts used in the product formulations beyond
the levels listed in the IID, or if the amount listed in the database is used in a therapeutic category that would not support the use of the same ingredi-ent in the proposed therapeutic oral dosage form, may require additional studies.
Aspartame (methyl ester of phenylalanine) is an artificial sweetener used in a number of CDER-approved oral drug products but requires a warn-ing on the label, because it is a source of phenylala-nine and a possible concern for phenylketoneurics. Thus its use should be carefully assessed in the product development and should be avoided where possible to mitigate this risk to a sub-set of the general population (55–57).
Bitter or unpleasant taste of pharmaceuticals is one of the causes of non-compliance and often leads to failure of the treatment in a variety of pa-tient populations. Because of this crucial papa-tient
compliance concern, it is necessary to address the issue of palatability through proper selection of in-gredients during development of the drug product formulation. Presently a number of approaches are used for taste-masking such as inclusion of sweet-eners and flavors, coating with pH sensitive poly-mers which are insoluble in the mouth but dissolve readily in the stomach, inclusion complexes, and complex of drug with ion-exchange resins. These taste-masking techniques have been successfully exploited in several dosage forms such as liquids, fast dissolving films, matrix formulations, and wet granulated formulations.
References
1. Webster’s Ninth Collegiate Dictionary (Merriam-Webster Inc., 1988).
2. E.T. Rolls, et al., Annals of the New York Academy of
Sciences 855 (1), 426-437 (1998).
3. Umami Information Center, www.umamiinfo.com
4. D. Baguley, et al, Arch. Dis. Child. 97, 293-297 (2012).
5. J.I.M. Glendinning, Physiology & Behavior. 56(6),
1217-1227 (1994).
6. WHO, “Drug Resistance: HIV/AIDS,” World Health Organization, www.who.int/drugresistance/hivaids/en/
7. B. Hovstadius and G. Petersson, BMC Health
Ser-vices Research 11: 326 (2011).
8. D. Lin, J.A. Seabrook, D.M. Matsui, S.M. King, M.J.
Rieder and Y. Finkelstein, Pharmacoepidemiology
and Drug Safety, 20(12): 1246–1252 (2011).
9. S. Winnick, et al, Pediatrics, 115(6), e718-e724
(2005).
10. E. Schirm, et al, Acta Padeiatr. 92(12), 1486-1489
(2003).
11. Committee for Medicinal Products for Human Use: Reflection Paper: Formulations of Choice for the Pediatric Population. EMEA/CHMP/
PEG/194810/2005.
12. A. Cram, et al, Int. J. Pharm. 365 (1-2), 1–3 (2009).
13. T.L. Reiland and J.M. Lipari, “Flavors and Flavor
Modifiers” in Encyclopedia of Pharmaceutical
Tech-nology, James Swarbrick Ed. (informa healthcare, 3rd ed., 2006), pp. 1763-1772.
14. G. P. McNally, and A. M. Railkar, “Formulation
Pediat-Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2015 23
ric Drug Development: Concepts and Applications,
An-drew E. Mulberg, Dianne Murphy, Julia Dunne, and Lisa L. Mathis, Eds. (John Wiley & Sons. 2nd ed., 2013), pp. 565-575.
15. S. Niazi, and A. Shamesh, “Chewing gum containing a medicament and taste maskers,” US Patent 04639368, Jan. 1987.
16. Y. Katsuragi, et al, Pharm. Res. 12 (5), 658-662 (1995). 17. C.M. Blase, and M.N. Shah, “Taste masked
pharmaceu-tical suspensions for pharmaceupharmaceu-tical actives,” Eur. Pat. Appl. EP0556057, August 1993.
18. A.T.P. Skraanga, and R.E. Tully/ Akzo Nobel, N.V., “Oral liquid antidepressant solution,” U.S. Patent
6,040,301, March 2000.
19. Y. Fu, S. Yang, et al., Therapeutic Drug Carrier Sys-tem,21(6), 433-475 (2004).
20. R.K. Chang, et al, Pharm. Technol. N. Am. 24(6), 52–58 (2000).
21. R.K. Khankari, et al., Cima Labs. Inc., “Rapidly dissolv-ing tablet dosage form,” US Patent 6,221,392, April 2001.
22. T. Mizumoto, Y. Masuda, and M. Fukui, Yamanouchi Pharmaceutical Co., Ltd., “Intrabuccally dissolving compressed moldings and production process thereof,” US Patent 5,576,014, November 1996.
23. F. Cilurzo, et al, Drug Dev. Ind. Pharm. 37(3), 252–259 (2011).
24. R. Mishra, and A. Amin, Pharm. Tech. 33(2), 48-56 (2009).
25. J.C. McElnay and C.M. Hughes, “Drug Delivery: Buc-cal Route,” in Encyclopedia of Pharmaceutical Technol-ogy, J. Swarbrick, Ed. (Marcel Dekker Inc., New York, NY, 3rd ed., 2006), pp. 1071-1081.
26. Y.D. Yan et al., Biol. Pharm. Bull. 33 (8), 1364-1370
PharmSciTech, 8(2), E127-E133 (2007).
30. D.S. Jones, “Chitosan” in Handbook of Pharmaceutical
Excipients, R.C. Rowe, P.J. Sheskey, and M.E. Quinn
Eds. (Pharmaceutical Press and the American Pharma-cists Association, Washington DC., 6th ed. 2009), pp. 159-161.
31. D. Bora, et al, AAPS PharmSciTech, 9(4), 1159 –1164 (2008).
32. Y. Paul, S. Tyagi, and B. Singh, Int. J. Pharma and Bio
Sciences, 2 (2), 20-30 (2011).
33. T. Ishikawa, et al, Chem. Pharm. Bull. 47(10), 1451‐1454 (1999).
34. J.W. Mauger, and D.H. Robinson, The Board of Re-gents of the University of Nebraska, “Coating tech-nology for taste-masking orally administered bitter drugs,” US patent 5728403 A, Oct. 1994.
35. A. Vaziri, and B. Warburton, J. Microencapsul. 11(6), 641-648 (1994).
DOI: 10.1208/s12249-008-9137-6
39. G. M. Roy, Pharm. Tech. 18, 84-99 (1994). 46. D. Yu and E. Roche, “Taste masked pharmaceutical liquid formulations” US Patent 6586012, Jul. 2003. 47. R. Cohen, et al, Eur. J. Pediatr. 168, 851–857 (2009). 48. A. Legin, et al, “Electronic tongues: new analytical perspective for chemical sensors,” In Integrated
Ana-lytical Systems, S. Alegret, Ed. (Elsevier, Amsterdam,
Vol. 39, 2003), pp. 437-486.
49. L.M. Schmidtke, et al., J. Agric. Food Chem., 58 (8),
54. M. Maniruzzaman, et al, Eur. J. Pharm. Biopharm.
80(2), 433-442 (2012). 55. Title 21 CFR 201.21
56. FDA, Drugs, FDA.org, www.fda.gov/Drugs/Informa-tionOnDrugs/ucm113978.htm
57. FDA, Guidance for Industry, Orally Disintegrating
Tablets (CDER, December 2008),
O
ral drug delivery is the preferred route of administration because it is convenient, relatively painless, and ame-nable to patients varying in age and cultural background (1). However, a challenge in formulating oral dosage forms results from a growing prevalence of higher molecular weight, poorly soluble compounds designed during drug discovery screen-ing. The coupling of combinatorial chemistry with high-throughput screening of ligand candidates for lipophilic receptor therapies has resulted in a predominance of poorly soluble new chemical entities (NCEs) and APIs (2–4).Solubility is crucial for any oral solid dosage form as the API must be released, dissolve in aqueous gastrointestinal media, traverse the endothelial barrier, and bypass metabolic enzymes to reach systemic circulation and deliver the drug’s intended pharmacotherapeutic ef-fect. If the API does not dissolve, it will be wasted, passing through the gastrointestinal tract without serving its intended pharmacologi-cal purpose. The development of safe and efficacious dosage forms containing poorly soluble APIs, therefore, represents a formidable challenge for formulation scientists.
Within the past 29 years, the amorphous solid dispersion (ASD) platform has gained popularity. An ASD is a metastable system that enables supersaturated dissolution of the API above its equilibrium solubility, making more of the delivered dose available for systemic absorption. Cellulose derivatives have emerged as leading polymeric excipients in ASD formulations, because they provide a matrix into which the amorphous API is dispersed and stabilized. They also in-hibit precipitation, maintaining the API at a supersaturated
concen-Using Polymers for
More Efficient Hot-Melt
Extrusion and Spray Drying
Kevin P. O’Donnell, William W. Porter III, and True L. Rogers
New cellulosic polymers have been shown to
improve solubility in these key amorphous solid dispersion processes.
tration once dissolved, which is referred to as the “spring-and-parachute” phenomenon (5). In addi-tion, cellulose derivatives are sustainable polymers derived from wood and cotton linters, and most are generally regarded as safe (GRAS) for human consumption.
Hot-melt extrusion and spray drying have emerged as the leading ASD technologies. For HME, the polymer must be brought to a softened or mol-ten state, so that the API can be dispersed within the polymer matrix while the combination of heat and shear render it amorphous.
Ideally, the API melts or dissolves in the molten polymer and is intimately mixed into the mass as it traverses through the conveying and kneading zones. The mixture then exits the extruder and can be pelletized, milled, calendared, or left as a strand or film.
In addition to softening or melting, the polymer used in hot-melt extrusion must be able to with-stand high shear and elevated temperature environ-ments. Once softened or molten, the polymer must also provide sufficient melt viscosity to create work-ability and some of the structural resistance neces-sary to knead and traverse the mass through the extruder and to mold the final form. The polymer should also allow the API to supersaturate in aque-ous media. Few polymers are available that are melt processable, stable during extrusion, stabilize the amorphous API, and enable API supersaturation.
Spray-dried dispersions are produced by dissolv-ing the API and cellulose derivative in an organic solvent or co-solvent mixture, then atomizing the solution into fine droplets in a drying chamber. The drying medium, typically heated nitrogen gas, evaporates the organic solvent, leaving the dry ASD to be collected in the cyclone.
Due to rapid solvent evaporation, spray-dried dispersions achieve intimate mixing of API and polymer, ideally delivering a molecular dispersion. These dispersions are also flowable and compress-ible for downstream processing, for example, com-pression to tablets.
Considering the challenges of making higher quality, safer, and more efficacious medicines available to a growing global population, ASD manufacturing processes must be robust and sus-tainable. Hydroxypropyl methylcellulose (HPMC) and hydroxypropyl methyl cellulose acetate suc-cinate (HPMCAS) polymers developed to work in hot-melt extrusion, spray drying, and other ASD processes are examined in this article.
Hot-melt extrusion
The scale of hot-melt extrusion technology allows for rapid throughput at production level, with a small manufacturing footprint. The number of available excipients for hot-melt extrusion is lim-ited, however, due to the aforementioned high tem-perature and shear exposure during the process.
Spray drying, like
hot-melt extrusion, offers
benefits in the formation
of solid dispersions.
Spray-dried dispersions
Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2015 27 HPMC has historically been
disadvantaged in hot-melt extrusion due to a narrow processing range between the glass transition temperature (Tg) and degradation temper-ature and high-melt viscosity (6), resulting in low through-put and typically requiring significant plasticization.
A f f i n isol HPMC (Dow Chemical) for hot-melt ex-trusion has a Tg of approxi-mately 115 °C, a lower melt viscosity and is stable to 200 °C while exhibiting minimal color change (7) allowing it to be extruded without plas-ticizer over a range of pro-cessing conditions at higher t hroughput. This perfor-mance was demonstrated by extruding neat polymer of varying viscosity grades,
from 100- to 4000-cP on a 26-mm Coperion hot-melt extruder at 155 °C into a translucent strand while utilizing 50% of system pressure and 30% of torque limits. This variance of polymer viscosity allows flexibility and control of the dissolution profile, as well as significant nucleation inhibition and supersaturation.
Griseofulvin (GRIS), a BCS Class II antifungal with a high melting point of 220 °C, was formu-lated with the 100 and 4M cP viscosity grades of Affinisol HPMC for hot-melt extrusion, as well as high and low experimental viscosity grades at a drug load of 10%.
The binary mixtures were extruded on a Leis-tritz Nano 16 hot-melt extruder at 180 °C, and the extrudate, using a low viscosity grade, was milled into a fine powder, while the extrudates contain-ing the 100 cP, 4M, and experimental high viscos-ity grade were pelletized. All extrudates were vis-ibly clear, and determined to contain amorphous GRIS by differential scanning calorimetry, pow-der x-ray diffraction, and Raman spectroscopy. The presence of a single Tg indicated a single-phase system.
Figure 1 shows that the low viscosity grade extru-date provided immediate release and supersatura-Figure 1: Dissolution of Griseofulvin from milled extrudate (low-viscosity HPMC HME) polymers.
Figure 2: Griseofulvin release from pelletized extrudates of various viscosity grades.
tion of the poorly soluble API and that the polymer successfully held the drug in solution for six hours.
Figure 2 shows how viscosity grade selection impacts
the supersaturated dissolution profile, from immedi-ate- to sustained-release. In all cases, the polymer not only controlled GRIS release but also maintained the dissolved drug in solution for up to 24 hours.
Itraconazole (ITZ), another poorly soluble BSC Class II compound, has been melt extruded with
HPMC to produce solid dis-persions. Although the litera-ture indicates that the API can plasticize the polymer, these formulations still required elevated processing tempera-tures of 180 °C (8, 9). Affinisol hot-melt extrusion polymers were formulated with ITZ at a 25% drug load and extruded at temperatures as low as 155 °C into translucent strands with experimental viscosity grades. As demonstrated in
Figure 3, drive load was low for
all formulations.
All strands were milled to fine powder, and the charac-terizations mentioned in the GRIS case study confirmed that ASDs were obtained. Similar to GRIS, the viscosity grade controlled the rate of ITZ supersaturation in acidic media, as shown in Figure 4. Ultimately, ~17X supersatu-ration of the equilibrium ITZ solubility was attained with all milled extrudates regardless of the viscosity grade of polymer used.
Itraconazole solubility is pH-dependent, and maintaining the drug in solution upon transition from simulated gastric to intestinal media is criti-cal for bioavailability improvement (10). Therefore, a pH change dissolution study was performed on ITZ formulated with relevant grades of Affinisol polymers and compared to an equivalent dose of
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commercial ITZ (Sporanox). The formulations were first exposed to acidic media for two hours and then buffer was added to raise the pH to 6.8. Figure 5 demonstrates that both the commercial ITZ formulation and the Affinisol extrudate pro-vided significant supersaturation in acidic media and maintained that supersaturation following the pH transition.
These case studies demonstrate Affinisol HPMC’s ability to be extruded over a range of
viscosities to enable success-ful extrusion of ASDs that can deliver immediate and sustained supersaturation of poorly soluble APIs.
Spray-drying applications Spray drying, like hot-melt extrusion, offers benefits in the formation of solid dis-persions: minimal thermal exposure, tunable particle morpholog y, solvent f lex-ibility, and the ability to post process the powder into the desired dosage form.
Despite these advantages, the operation in pharmaceu-tical development has been mired by scalability issues, with commercial spray dryers requiring large manufactur-ing footprints and substantial resources for production. One factor determining a large footprint is that spray drying is a viscosity-limited process with solution viscosity primarily controlled by the enabling excipient.
Hypromellose is available in a number of sub-stitution chemistries and viscosity grades. HPMC 2910 is the most commonly used grade of HPMC for spray drying, as it has the highest organic sol-ubility of the pharmacopeial substitution grades. Low viscosity HPMC 2910 is typically utilized to prevent viscosity associated atomization issues.
Affinisol HP polymers were developed with Figure 5: Dissolution of Itraconazole following a pH transition dissolution method. Buffer
addition point is denoted by the vertical red line.
Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2015 31 lower viscosity than standard
HPMC 2910, to increase the dissolved solids concentration while still achieving a solution viscosity that can be atomized.
Figure 6 shows the concen-tration-dependent viscosity of Affinisol HP HPMC and Methocel E3 at shear rate of 100 s-1, demonstrating that up to 1.5 times more solids could be dissolved in the spray solu-tion, thus increasing product payload during spray drying.
Affinisol HP HPMC main-tained its ability to supersat-urate and inhibit nucleation of poorly soluble APIs to the same degree as standard HPMC 2910 in tests. Spray- dried dispersions contain-ing 10% ketoconazole or 10% phenytoin were made with Methocel E3 and Af-finisol HP HPMC on a Bend miniSD spray dr yer, and evaluated by a
microcentri-fuge dissolution test (MCT) (11) to compare su-persaturation performance. The spray solutions containing Affinisol HP HPMC contained 1.5 times the amount of solids as the solutions con-taining Methocel E3.
The MCT dissolution plots, Figure 7, dem-onstrate that the dispersions created with Af-finisol HP HPMC achieve the same level of su-persaturation and nucleation inhibition as the standard grade.
Although traditionally used for enteric applica-tions, HPMCAS has found utility as a solubility-enabling excipient and is available in three grades that vary by acetate and succinate substitution. Unlike HPMC, standard HPMCAS has no varia-tion within each grade based on viscosity of the polymer.
The reduced viscosity of Affinisol HP HPMCAS compared to standard HPMCAS (Figure 8) allows for an increase in solids loading in the spray
lution of up to 1.7 times the standard HPMCAS material.
Spray-dried dispersions were formed as de-scribed previously using either Affinisol HP HPM-CAS or standard HPMHPM-CAS and phenytoin, itra-conazole, and ketoconazole as model APIs, with all spray solutions made at 2% solids with 25% (w/w) API loading.
The spray-dried dispersions were analyzed by MCT dissolution testing, and the AUC90 values
were compared for each com-pound. As shown in Figure 9, Affinisol HP HPMCAS and standard HPMCAS deliver nearly identical supersatura-tion for each model API. Vari-ations seen in Figure 9 highlight that formulation optimization may be required when switch-ing from standard HPMCAS to Affinisol HP HPMCAS. The reduced viscosity of the spray solution when a one-to-one substitution of standard HPMCAS with Affinisol HP HPMCAS will impact atomi-zation at the spray nozzle and, thus, particle formation.
While spray drying is tradi-tionally a process with a large footprint and low through-put, excipients designed spe-cifically for this operation can reduce the footprint, cost, or even scale of spray dryer needed.
References
1. D.W.A Bourne, PHAR 7633, Chapter 7: Routes of drug adminis-tration (2010) pp. 1-14.
2. M.A. Repka, American Pharm Rev. Volume 1-10 (2009). 3. M. Maniruzzaman, et al., ISRN Pharm, 1-9 (2012). 4. T. Bee. and N. Neub, Manuf Chem Pharm, April, 1-7 (2011). 5. H.R. Guzman et al., J Pharm Sci, 96 (10), 2686-2702 (2007). 6. O.A. Abu-Diak, D.S. Jones, and G.P. Andrews, Molecular
Phar-maceutics 8(4) 1362-1371 (2011).
7. K.A. Coppens, et al., Pharm Tech, January, 62-70 (2006). 8. K. P. O’Donnell and W.H.H. Woodward, Drug Dev Ind Pharm.
May 20:1-10 (2014).
9. K. Six, et al., Pharmaceutical Research 20(7) 1047-1054 (2003). 10. D.A. Miller, et al., Drug Dev Ind Pharm. 34, 890-902 (2008). 11. D.T. Friesen, et al., Mol. Pharm. 5 (6) 1003-1019 (2008). PT Figure 8: Rheology of acetone solutions containing 20% (w/w) Affinisol HP HPMCAS
polymers needed and Affinisol HPMCAS.
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At Metrics, We Also Keep
T
he workflows associated with the development of an oral solid dosage (OSD) product, whether innovator or generic, focus on detailed characterization of the API and excipi-ents, both individually and then in combination, within the blended formulation. Processing steps such as blending can alter the characteristics of an API, thereby affecting the efficiency of a drug’s delivery or its clinical efficacy. The ability to identify and measure the critical material attributes of the API and the excipients separately prior to processing, and also within a multicomponent blend, is essential.This article considers the analytical information required to drive formulation workflows, focusing on the use of laser diffraction par-ticle size analysis, gel permeation/size exclusion chromatography (GPC/SEC), and morphologically directed Raman spectroscopy (MDRS). These techniques play a role in the efficient characteriza-tion of APIs and excipients, separately and when blended.
Regulatory framework for OSD formulation
The OSD form is the most widely used drug delivery vehicle, and the workflows associated with its development are well defined. Interna-tional Conference on Harmonization (ICH) Q8 (R2) Pharmaceutical Development (1) describes these workflows and highlights the steps needed to ensure success, which include:
• Definition of the quality target product profile (QTPP)
• Identification of the critical quality attributes (CQAs) of the product
• Determination of the CQAs of the drug substance
and excipients
• Selection of an appropriate manufacturing process
• Definition of a control strategy.
Analytical Techniques for
Oral Solid Dosage Formulation
Paul Kippax and Deborah Huck-JonesAnalytical technologies must accurately identify and measure the critical material attributes of APIs and excipients, separately and when combined during oral solid dosage formulation and development.
Pharmaceutical Technology SOLID DOSAGE & EXCIPIENTS 2015 35
The starting point for formulation is definition of the performance that the product must deliver, the QTPP. This definition relates to clinical effi-cacy, quality, and safety, and involves the consid-eration of such issues as drug strength, bioavail-ability, and the rate of drug delivery. The CQAs of the product are the product variables that have a direct impact on the QTPP, and, for an OSD prod-uct, might include such parameters as disintegra-tion rate, dose uniformity, and hardness.
Delivering the CQAs of the product relies on es-tablishing the CQAs of the drug substance and ex-cipients of the formulation, the individual compo-nents of the formulation. Systematic investigation of the individual excipients and APIs is required to determine which of their properties is linked with control of the product CQAs and/or delivery to the QTPP. A CQA for the product, for example, might be its disintegration characteristics, while an associated CQA for the API could be particle size, since this influences the bioavailability of an API when it is released from the tablet matrix.
Once the performance of the individual API and excipient has been investigated, there is a require-ment to assess whether the individual components are changed as the blend is formulated and
pro-cessed. At this stage, the focus shifts from look-ing at individual look-ingredients to characterization of the blend and the development of an appropri-ate manufacturing process. Putting in place the monitoring and control strategies needed to ensure consistent manufacture marks the endpoint of the development process.
The prevailing influence of quality by design (QbD) is evident from the language used to define this workflow. However, there is no regulatory re-quirement to apply QbD when working toward a new drug application (NDA). For abbreviated new drug applications (ANDAs), basic QbD prin-ciples, as set forth in FDA’s question-based review approach, are required. Applying QbD does not change the underlying formulation workflow, but it does influence the rigor with which each stage is implemented.
A QbD approach to investigating the CQAs of the API, for example, might extend to develop-ing functional relationships between these CQAs and critical material attributes (CMAs) and criti-cal process parameters (CPPs), rather than simply identifying appropriate ranges for the CQAs. A QbD approach to process development is based on scoping the design space—an operating window in which success is assured—rather than simply defining a fixed set of processing conditions. This rigor creates a requirement for more extensive in-formation gathering and intensifies the need for appropriate analytical strategies.
Focusing on the API
In the early stages of formulation, the focus is very much on the API and how its therapeutic effect can be most efficiently delivered to the patient. ICH Q6A, Specifications: Test Procedures and
Accep-A
tance Criteria For New Drug Substances and New Drug Products: Chemical Substances (2) details the biological and physicochemical properties that can influence the pharmacological profile of an API, which include:
• Physical properties such as pH, refractive index, melting point
• Particle size
• Polymorphic form/amorphous content
• Chiral identity
• Water content
• Inorganic impurity levels
• Microbial content.
Assessing the impact of these properties helps with the development of a detailed specification for the API. Some of these properties are relatively easy to measure, but for others analysis is more dif-ficult. For example, particle size can be measured quickly and easily for all types of pharmaceutical products using the technique of laser diffraction. Polymorphic form, on the other hand, is less read-ily characterized.
Many APIs exist in multiple crystal forms and these have the potential to exhibit different clini-cal performance. If a certain polymorph is identi-fied as having desirable characteristics, then it is essential to verify that the correct polymorphic form is used in the formulation and is delivered by the manufacturing process. Manual micros-copy is one technique for differentiating crystal forms but it can be both time-consuming and subject to operator variability. Morphologically directed Raman spectroscopy (MDRS), a rela-tively new technique, enables quicker and more accurate polymorph detection.
MDRS involves using morphological data to guide the application of Raman spectroscopy, which in turn provides chemical identification. The process is implemented using an automated imaging system with spectroscopy capabilities.
Differentiating API polymorphs
Automated imaging (Morphologi G3-ID) was used to characterize two different polymorphic forms of an API. Polymorph A was found to have a square-like crystalline form, while poly-morph B exhibited a needle-like structure (see
Figure 1). This difference in morphology meant
that by applying size and shape classification to the automated imaging data, it was possible to
Figure 2: Raman spectra for polymorphs A (orange line) and B (red line) show clear differences between 1120–1300 cm-1.
